This invention relates to potassium channel activators in the form of thienopyran compounds, preparations and compositions containing them, and their use in mammalian hair growth modulation.
Potassium channels (K+ channels) are important cell function regulatory sites. There appears to be a diversity of such channels. Interest in them as sites of therapeutic intervention has increased in recent years (Cook, N. S., Potassium Channels: structure, classification, function and therapeutic potential, Ellis Horwood Ltd., 1990).
Compounds which act as potassium channel activators (potassium channel openers) are known. Research in the area was stimulated by the discovery of cromakalim (described in EP-A-76075), which has a benzopyran-based structure, but the molecular details which cause the activity are not yet elucidated.
U.S. Pat. No. 5,077,307 discloses certain potassium channel activators having a thienopyran ring structure. Specifically, the following two compounds are disclosed: 
where X is xe2x80x94CN and xe2x80x94CONH2. The hydroxy and oxopyrrolidinyl groups at the 6,7 positions have a trans orientation. The first of these (with X=CN) is disclosed in U.S. Pat. No. 5,077,307 in its racemic form and as each of its enantiomers. The racemic form is referred to below as compound 11901, and the (xe2x88x92)-enantiomer as compound 11903.
Other substituted thienopyrans useful as anti-hypertensive agents and for other purposes are disclosed in U.S. Pat No. 5,284,857.
The object of the invention in to provide new and useful compounds which have potassium channel activating. activity.
According to the invention in a first aspect there is provided a thienopyran compound having the formula I, II or III 
wherein
X is H or an electron-withdrawing group,
Y is an alicyclic or heterocyclic ring spiro-connected to the thienopyran ring at the position indicated by Y, the ring Y being saturated or mono-unsaturated and being substituted or unsubstituted,
Z is selected from hydrogen, hydroxy and alkoxy.
Preferably, X is H or an electron-withdrawing group selected from NO2, CN, halogen, halogenated alkyl, alkanoyl (C1-4), halogenated alkanoyl (C1-4) benzoyl, acylamino (C2-4), alkoxycarbonyl (C1-4), CHO, COOH, COOR where R is C1-4, CHxe2x95x90NOH, CONH2 CON(Rxe2x80x2)2 or NHCORxe2x80x2 where Rxe2x80x2 is alkyl (C1-4), alkoxy (C1-4) or phenyl, oxophosphorus and oxosulphur groups and 
More preferably, X is selected from xe2x80x94CN, halogenated alkyl (preferably of 1-4 C atoms), oxophosphorus or oxosulphur groups (preferably xe2x80x94SO2R1 or PO(OR2), where R1 is substituted or unsubstituted phenyl, pyridyl or thienyl and each R2 is H or alkyl of 1-4 C atoms), oxocarbon groups (e.g. xe2x80x94CHO, xe2x80x94CONR32, xe2x80x94COOR3, wherein each R3 is H or alkyl of 1-4 C atoms) and xe2x80x94CHxe2x95x90NOH,
Ring Y is preferably 
wherein Q is selected from saturated and mono-unsaturated carbon chains of 2-4 carbon atoms, and A and B fulfil one of the following; (a) both being carbon atoms, (b) one being S, SO or SO2, and the other a carbon atom, (c) each being S, SO or SO2, (d) one being NRxe2x80x3 where Rxe2x80x3 is hydrogen or alkyl and the other being a carbon atom, (e) each being NRxe2x80x3 where Rxe2x80x3 is hydrogen or alkyl; and each carbon atom of the ring Y is unsubstituted or substituted by one of alkyl, halogen or hydroxy or is a member of a carbonyl group or an epoxy ring.
More preferably Y is of the formula 
wherein
S1 is  greater than S,  greater than SO or SO2 and S2 is part of a carbon chain with Q or is  greater than S,  greater than SO or  greater than SO2, and Q is a saturated or unsaturated (preferably mono-unsaturated) carbon chain of 2-4 C atoms, each carbon atom of the heterocyclic ring being unsubstituted or substituted by alkyl (preferably of 1-4 C atoms), halogen or hydroxy, or is a member of a carbonyl group or an epoxy ring, and
Z is hydrogen, hydroxy or alkoxy (preferably of 1-4 C atoms).
Preferably X is xe2x80x94CN, and preferably Z is H.
Preferably Y is selected from the following: 
In a second aspect, the invention provides thienopyran compound having the formula I, II or III 
wherein
X is H or an electron-withdrawing group selected from xe2x80x94CN, halogenated alkyl (preferably of 1-4 C atoms), oxophosphorus or oxosulphur groups (preferably xe2x80x94SO2R1 or PO(OR2)n where R1 is substituted or unsubstituted phenyl, pyridyl or thienyl and each R2 is H or alkyl of 1-4 C atoms), oxocarbon groups (e.g. xe2x80x94CHO, xe2x80x94CONR32, xe2x80x94COOR3, wherein each R3is H or alkyl of 1-4 C atoms), xe2x80x94CHxe2x95x90NOH and 
xe2x80x83and
A is 
wherein B is a saturated or unsaturated carbon chain of 2-4 C atoms of which each carbon atom is unsubstituted or substituted by alkyl (preferably of 1-4 C atoms), halogen or hydroxy, or is a member of an epoxy ring.
Preferably X is xe2x80x94CN, and preferably A is selected from the following: 
In a third aspect, the invention provides a thienopyran compound having the formula I, II or III 
wherein
X is selected from oxophosphorus and oxosulphur groups (preferably xe2x80x94SO2R1 or PO(OR2)n where R1 is substituted or unsubstituted phenyl, pyridyl or thienyl and each R2 is H or alkyl of 1-4 C atoms), and
D is 
wherein B is a saturated or unsaturated carbon chain of 2-4 C atoms of which each carbon atom is unsubstituted or substituted by alkyl (preferably of 1-4 C atoms), halogen or hydroxy, or is a member of an epoxy ring.
Preferably X is xe2x80x94SO2(C6H5), and preferably D is 
In all three of the above aspects of the invention, the preferred compounds are those having the formula I.
The invention also provides a pharmaceutical preparation comprising a thienopyran compound of the first three aspects above.
Further the invention provides a composition for administration to a human or other mammal, comprising as active ingredient a thienopyran compound of the first three aspects above, particularly a composition effective for hair growth modulation in a human or other mammal.
The results in the K+-stimulated isolated rat aorta test given below indicate that the compounds of the invention are potentially useful as anti-hypertensive agents to reduce blood pressure in mammals and also to reduce the immunological response associated with asthma.
As discussed below, it has been found that thienopyran compounds herein described have indications for activity for modulation of mammalian hair growth. Accordingly in another aspect the present invention consists in use of certain thienopyran compounds for hair growth modulation, including known compounds proposed for other purposes as described above. Particularly the invention provides cosmetic hair growth modulation, but hair growth modulation for non-cosmetic purposes is not excluded. In this aspect the invention provides a method of modulation of hair growth in a human or other mammal, comprising topical application of a thienopyran compound (including partially saturated thienopyran compounds, e.g. dihydro thienopyrans) which has activity of hair growth modulation in an amount effective to provide hair growth modulation.
More specifically in this aspect the invention provides a method of modulation of hair growth in a human or other mammal, comprising topical application of an effective amount of at least one thienopyran compound having the formula I, II or III 
and A1 and A2 are selected from hydrogen, nitro, cyano, trifluoromethyl, halogen, lower alkyl (C1-4), alkanoyl (C2-4), substituted alkyl (C1-4) and substituted alkanoyl (C2-4), wherein the substituent is halogen; benzoyl, substituted benzoyl, wherein the substituent is selected from bromo, chloro, iodo, alkyl (C1-4), alkoxy (C1-4), acyl (C2xe2x88x92), nitro, cyano and trifluoromethyl; acylamino (C2-4), alkoxy carbonyl (C1-4), CHO, COOH, CHxe2x95x90NOH, CONH2, CON(R)2 and NHCOR wherein R is alkyl (C1-4), alkoxy (C1-4), phenyl or substituted phenyl wherein the substituent is selected bromo, chloro, iodo, lower alkyl, lower alkoxy, nitro, cyano, trifluoromethyl and acyl (C2-4); oxophosphorus and oxosulphur groups; and 
A3 and A4 are selected from hydrogen, hydroxy, alkanoyl (C2-5), alkyl (C1-4), cycloalkyl (C3-6), cycloalkyl carbonyl (C3-6), pyridyl carbonyl, benzoyl, substituted benzoyl wherein the substituent is selected from bromo, chloro,iodo, alkyl (C1-4), alkoxy (C1-4), acyl (C2-4), nitro, cyano and trifluoromethyl; or A3A4N together are a heterocyclic ring selected from a pyrrole, pyrrolidine or piperidine ring, a (C3-9) lactam selected from the group consisting of isoindolone, pyrrolidinone, piperidinone, pyridinone, pyrazinone, and glycine anhydride, or substituted (C3-9) lactam; A5 is hydrogen or together with A6 forms a double bond; M is CH or taken together with A, is carbonyl; A6 is hydrogen, hydroxy, alkoxy (C1-6), alkanoyloxy (C2-7), benzoyloxy, substituted benzoyloxy; and A7 and A8 are hydrogen or alkyl (C1-4) or together form a ring having 5-8 carbon atoms; and optical isomers thereof.
Preferred in this aspect of the invention are compounds in which one of A1 and A2 is H, A5 is H, A6 is OH, A7 and A8 are CH3 and A3A4N together are a lactam.
The contents of U.S. Pat. Nos. 5,284,857 and 5,030,736 are herein incorporated by reference for their disclosure of particular compounds and their syntheses.
The invention also consists in a method of preparing a composition for use in modulation of hair growth in a human or other mammal by topical application, comprising the step of incorporating in a dermally acceptable formulation at least one of thienopyran compound, more particularly those herein defined.
In accordance with the present invention, compositions provided may be administered to human individuals or used as a veterinary medicine, particularly for other mammals. Administration is preferably in a xe2x80x9ctherapeutically effective amountxe2x80x9d, this being sufficient to show benefit to a patient. Such benefit may be at least amelioration of at least one symptom. The actual amount administered, and rate and time-course of administration, will depend on the nature and severity of what is being treated. Prescription of treatment, eg decisions on dosage etc, is within the responsibility of general practitioners and other medical doctors.
Pharmaceutical compositions according to the present invention, and for use in accordance with the present invention, may comprise, in addition to active ingredient, a pharmaceutically acceptable excipient, carrier, buffer, stabiliser or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material will depend on the route of administration, which may be oral, or by injection, e.g. cutaneous, subcutaneous or intravenous.
Pharmaceutical compositions for oral administration may be in tablet, capsule, powder or liquid form. A tablet may comprise a solid carrier such as gelatin or an adjuvant. Liquid pharmaceutical compositions generally comprise a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such an ethylene glycol, propylene glycol or polyethylene glycol may be included.
For intravenous, cutaneous or subcutaneous injection, or injection at the site of affliction, the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, tonicity and stability. Those of relevant skill in the art are well able to prepare suitable solutions using, for example, isotonic vehicles such as Sodium Chloride Injection, Ringer""s Injection, Lactated Ringer""s Injection. Preservatives, stabilisers, buffers, antioxidants and/or other additives may be included, as required.
When used for mammalian hair growth modulation, i.e. hair growth stimulation or hair growth inhibition, the thienopyran compounds may be administered to the skin topically, i.e. at the growth site. For this purpose a composition containing the active thienopyran compound or compounds is prepared, containing also appropriate dermally acceptable formulating ingredients, such as oil, emulsifying agent, skin permeation enhancer, liposomes, perfume, and a solvent (such as alcohol and propylene glycol).
All stereo isomers, including optical isomers, of any compounds disclosed herein are included within the invention.
An alkyl group herein is preferably lower alkyl. Lower alkyl means C1-4 unless otherwise specified.
When a group or atom is described as substituted it may be substituted by any of OH, halogen, lower alkyl, alkoxy (C1-4), nitro cyano and haloalkyl (C1-4).